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Chapter 8
The presynaptic neuron releases neurotransmitter into a narrow space (30 - 50 nm) between the cells
called a synaptic cleft. The neurotransmitter is contained in synaptic vesicles and is released by
exocytosis. The neurotransmitter effects a change in the postsynaptic cell by a mechanism called
signal transduction.
Concentrated at the axon terminal are voltage-gated calcium channels. The depolarization of the
membrane associated with an action potential causes the calcium channels to open and Ca++ rushes
down its electrochemical gradient. Ca++ causes the membranes of the synaptic vesicles to fuse with the
cell membrane and releases its contents by exocytosis. (Go to the chemical synapse link on this site for
an animation.)
The Ca++ influx stops within a few msecs when the Ca++ channel close. However, when a series of
action potentials arrives at the axon terminal there is a greater inflow of Ca++ and more
neurotransmitter is released. Hence, the higher the frequency of action potentials the greater the
amount of neurotransmitter released.
The neurotransmitter is a ligand that binds to a receptor protein. The neurotransmitter needs to be
removed to end the signal and clear the way for the next signal.
Processes for Neurotransmitter Removal Norton books animation
1. Diffusion - Neurotransmitter may simply diffuse away.
2. Re-uptake - The presynaptic neuron may actively transport the neurotransmitter back into
itself.
3. Enzymatic Destruction - Enzymes located in cell membranes of pre- and postsynaptic cells
or glial cells may breakdown the neurotransmitter.
It takes about 0.5-5 msec from the time of arrival of the action potential to a response in the
postsynaptic cell this is called a synaptic delay and is due primarily to the time it takes for
calcium to trigger exocytosis.
Signal Transduction Mechanisms
Neurotransmitters can produce either a fast or a slow response. Fast response involves ionotropic
receptors where the neurotransmitter binds to a channel-linked receptor. All channel-linked receptors are
ligand-gated channels. The channel opens, the ions flow down their electrochemical gradients, and produce a
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brief change in membrane potential called a postsynaptic potential (PSP). Slow responses act by triggering
biochemical changes through G protein-linked receptors. These are called metabotropic receptors.
Activation of the G protein may either open or close an ion channel. The final effect depends upon the type
of ion channel. If the result is a depolarization the response is excitation; if the result is hyperpolarization
the effect is inhibition.
The G protein may either be directly coupled to an ion channel or may trigger the activation or inhibition
through a secondary messenger system. The duration of the response may range from msec to hours.
Excitatory Synapses
An excitatory synapse causes a graded potential that depolarizes the membrane and brings it
closer to threshold. The depolarization is an excitatory postsynaptic potential (EPSP) and may be
either fast or slow.
Fast EPSP's involve the opening of small cation channels (for K+ and Na+). Because there is a
larger influx of Na+ compared to K+ a net depolarization results.
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Slow EPSP typically involve the closing of K+ channels through the mediation of a G protein and
cAMP as a second messenger. The decrease in K+ permeability causes the net influx of positive
charge (associated with Na+) to increase which depolarizes the membrane. These EPSP take longer
to develop and last longer.
Inhibitory Synapses
An inhibitory synapse decreases the likelihood that an action potential will occur by either
hyperpolarizing the membrane or keeping it at the resting level.
At inhibitory synapses the neurotransmitter opens channels for either K+ or Cl- . Opening K+
channels causes K+ to leave the cell hyperpolarizing the membrane and creating an inhibitory
post-synaptic potential (IPSP). The effect of a neurotransmitter that opens Cl- channels depends
upon the electrochemical force acting upon Cl-.
In some neurons Cl- are actively transported out of the cell. This creates an equilibrium
potential for Cl- that is more negative than the resting potential. In these cells there is an
electrochemical force driving Cl- into the cell. When the Cl- channels are opened, Cl- goes into the
cell down its gradient and hyperpolarizes it (make it more negative).
In other neurons there is no active transport of Cl- and Cl- is at equilibrium. The way the
opening the Cl- channels in these cells is inhibitory is more complicated.
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The opening of the Cl- channels interferes with the ability of excitatory synapses to induce
EPSP's. This is because if the Cl- channels open at the same time as the cation channel that produces
an EPSP, Cl- moves into the cell as the membrane potential becomes more positive. The movement
of negatively charged Cl- then cancels out the change that would have resulted from the influx of
positive charges. As a result, the membrane potential does not change and threshold is not reached.
Neural Integration
The axon hillock of the postsynaptic neuron is influenced by the electrotonic conduction of all the
membrane potential changes produced by the various excitatory and inhibitory synapses. The net
change in membrane potential at the axon hillock that results from this process is called neural
integration. Whether or not the potential at the axon hillock reaches threshold depends upon the
additive effects of all the graded potentials. The graded potential can either add in time or space.
Temporal Summation
In temporal summation postsynaptic potentials at the same synapse occur in rapid
succession. Because the effect of the first potential does not have time to dissipate the
succeeding potentials add to the previous ones and increase the change in potential. Summation
can occur with IPSP's as well as with EPSP's.
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Temporal summation can occur because postsynaptic potentials last longer than action
potentials. Neurotransmitter released into the synaptic cleft by a previous action potential may
still be present when a succeeding action potential causes the release of more neurotransmitter.
Spatial Summation
In spatial summation multiple postsynaptic potentials from different synapses occur about
the same time and sum. The EPSP's of different synapses are not strong enough to generate an
action potential but by reinforcing one another may trigger an action potential. It is important to
keep in mind that EPSP's and IPSP's will also add up to cancel each other's effects.
Frequency Coding
Neural integration of postsynaptic potentials not only triggers action potentials but also affects the
frequency of action potentials when summation results in a suprathreshold potential. The
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relationship between the strength of suprathreshold stimuli and the frequency of action potentials is
called frequency coding.
Presynaptic Modulation
With axoaxonic synapses the neurotransmitter from the presynaptic neuron modulates the axon
terminal by affecting the amount of calcium that enters in response to an action potential.
Presynaptic Facilitation
Presynaptic facilitation results when an axoaxonic synapse causes an action potential
arriving at the postsynaptic axon terminal to release more neurotransmitter and thereby
cause a larger EPSP. Note that this type of synapse only influences the effect of another neuron
at its synapse with a postsynaptic neuron. In other words, presynaptic modulation will only
affect transmission to the postsynaptic neuron at one specific synapse.
Presynaptic Inhibition
In presynaptic inhibition the neurotransmitter from the presynaptic neuron at the axonic
synapse causes the postsynaptic axon terminal to release less neurotransmitter when an
action potential arrives.
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It is important to keep in mind that presynaptic modulation can affect inhibitory synapses as well
as excitatory synapses.
Neurotransmitters (Table 8.1)
Acetylcholine (ACh)
Found in both central and peripheral nervous systems. It is the most abundant
neurotransmitter in the peripheral nervous system. ACh is synthesized in the cytoplasm of the
axon terminal from two substrates, acetylCoA and choline, in a reaction catalyzed by choline
acetyl transferase.
ACh is stored in synaptic vesicles until an action potential causes its release by exocytosis.
ACh binds to receptors called cholinergic receptors and is degraded by acetylcholinesterase
(AChE), an enzyme that can be found in both the pre- and postsynaptic membranes. The
degradation products are acetate which enters the blood and choline which is taken up by the
presynaptic neuron and recycled.
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Neuroactive Peptides
Neuroactive peptides are short chains of amino acids. Many neuropeptides are known as
hormones such as:
TRH (thyroid releasing hormone) which releases TSH
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Vasopressin (ADH)
Oxytocin
Substance P
Endogenous opioids including enkephalins and endorphins
Most neuropeptides are secreted from the same axon terminals as other neurotransmitters and
act on metabotropic receptors to modulate the response of the postsynaptic neuron to the other
neurotransmitters.
Other Neurotransmitters
Nitric oxide cannot be stored as it easily crosses the cell membrane as soon as it is
synthesized. Its release is controlled by controlling its synthesis in a reaction catalyzed by nitric
oxide synthetase. NO acts by altering the activity of proteins.
ATP also serves as a neurotransmitter.
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